PROJECT SUMMARY/ABSTRACT After spinal cord injury (SCI), the injury site is filled with cellular debris, especially myelin debris that creates a very unique lipid-dense environment. Macrophages are the predominant phagocyte that are responsible for debris-clearance, but this process is not only inefficient, it is also maladaptive. The excessive amount of myelin debris present at the injury site leads to formation lipid-laden macrophages (a.k.a. foamy macrophages) that become pro-inflammatory and contribute to tissue regeneration failure. In addition to macrophages, microglia and fibroblasts also become foam cells. Therefore, understanding the mechanisms of myelin debris uptake and catabolism after SCI may lead to novel therapeutic targets to promote repair after SCI. In this application, we will investigate the mechanism of myelin debris uptake as well as the export of its catabolic byproduct in macrophages, microglia, and fibroblasts after SCI. In addition, we will test the therapeutic potential of novel nanoparticles that can target the uptake and efflux mechanisms.